METHODS:

Subjects self-reported symptoms using an anchored ordinal scale of 0 (no symptom), 1 (trivial complaints), 2 (mild), 3 (moderate), and 4 (severe). Fatigue of 3 or 4 distinguished "Fatigued" from "Not Fatigued" subjects. The sum of the 8(Sum8) ancillary criteria was tested as a proxy for fatigue. All subjects had history and physical examinations to exclude medical fatigue, and ensure categorization as healthy or CFS subjects.

RESULTS:

Fatigued subjects were divided into CFS with ≥4 symptoms or Chronic Idiopathic Fatigue (CIF) with ≤3 symptoms. ROC of Sum8 for CFS and Not Fatigued subjects generated a threshold of 14 (specificity=0.934; sensitivity=0.928). CFS (n=256) and CIF (n=55) criteria were refined to include Sum8≥14 and ≤13, respectively. Not Fatigued subjects had highly skewed Sum8 responses. Healthy Controls (HC; n=269) were defined by fatigue≤2 and Sum8≤13. Those with Sum8≥14 were defined as CFS-Like With Insufficient Fatigue Syndrome (CFSLWIFS; n=20). Sum8 and Fatigue were highly correlated (R(2)=0.977; Cronbach's alpha=0.924) indicating an intimate relationship between symptom constructs. Cluster analysis suggested 4 clades each in CFS and HC. Translational utility was inferred from the clustering of proteomics from cerebrospinal fluid.

CONCLUSIONS:

Plotting Fatigue severity versus Sum8 produced an internally consistent classifying system. This is a necessary step for translating symptom profiles into fatigue phenotypes and their pathophysiological mechanisms.

KEYWORDS:

Distribution of Sum8 for each Fatigue Score in Cohort 1 & 2. The study population was divided into not fatigued (HC), chronic idiopathic fatigue (CIF), and Chronic Fatigue Syndrome (CFS) groups. The nonfatigued group was defined by fatigue levels of 0 (none, red bars), 1 (trivial, gold bars) or 2 (mild, pink bars). The most frequent score was 0 for fatigue and 0 for Sum8 (13.1% of Cohort 1&2). The perspective was optimized to show the scatter of Sum8 for HC. The CIF group had fatigue scores of 3 (moderate, yellow cylinders) or 4 (severe, green cylinders) and ≤ 3 ancillary criteria with severity scores of 2, 3 or 4. The highest Sum8 score in the CIF group was 15. At this initial stage, CFS was defined by moderate (3, aqua bars) or severe (4, blue bars) fatigue plus at least 4 ancillary criteria with severities of 2, 3 or 4. Receiver operator analysis of Sum8 set the threshold between HC and CFS at 14 (blue arrow). The overall distribution of data was unique to Cohort 1&2 as this was not a population - based epidemiology study.

Sum of 8 ancillary symptom scores (Sum8). Sum8 scores for HC (n=259, yellow squares) and CFS (n=276, black diamonds) were plotted as a function of Fatigue Severity Score (means with 95% confidence intervals). The explained variance for Fatigue and Sum8 was 97.7%. Scores for the CFSLWIFS group (n=30, green triangles) were shown separately to indicate their “CFS-like nature”. Scores for the CIF group (n=31, blue circles) were not included in the linear regression.

Clusters based on CFS Severity Score components. Clusters within A. CFSLWIFS, B. HC, C. CFS and D. CIF are shown. The single clade with severity scores that were significantly different from all of the other clades in the group were indicated on each graph. For example, fatigue severity for HC clade “A” was significantly different from clades “B”, “C” and “D” with p<10-5 by Tukey’s test following ANOVA. (Ftg, fatigue; HA, headaches; Cog, memory and other cognitive problems; ExEx, exertional exhaustion; Myal, mayalgia; Arth, arthralgia; SThr, sore throat; LN, sore lymph node regions).